Central Nervous System Stimulants Analeptics -Respiratory stimulants & Convulsants. ... It stimulates respiration by action on peripheral carotid chemoreceptors. It has use as a respiratory

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College of Pharmacy 4th

Stage// Lecture 6 Medicinal Chemistry Dr.Narmin H.Amin

Central Nervous System Stimulants

CNS stimulants speed up mental and physical processes in the body. They increase

energy, attention, and alertness, and elevate blood pressure, heart rate and respiratory

rate.

CNS stimulants are still used to treat attention-deficit hyperactivity disorder (ADHD),

narcolepsy, and weight loss.

Analeptics -Respiratory stimulants & Convulsants.

Psychomotor stimulants- Excitement & Euphoria – Decrease feeling of fatigue &

increase motor activity.

Psychotomimetic (Hallucinogenic)- Changes in thought patterns & mood

Analeptics Drugs: The traditional analeptics are a group of potent and relatively nonselective CNS

stimulants. The convulsive dose lies near their analeptic dose.

Picrotoxin: Picrotoxinin, the active ingredient of picrotoxin, the hydroxylactonyl moiety is

mandatory for activity, with the 2-propenyl group assisting.

Picrotoxinin exerts its effects by interfering with the inhibitory effects of γ-

aminobutyric acid (GABA) at the level of the GABAA receptor’s chloride channel

(Block action of GABA …. Blocks Cl- Conductance).

It has been useful in determining mechanisms of action of sedative– hypnotics and

anticonvulsants. Butyrolactones bind to the picrotoxinin site.

Pentylenetetrazole(Metrazol): Pentylenetetrazole has been used in conjunction with the electroencephalograph

to help locate epileptic foci.

It is used as a laboratory tool in determining potencies of potential anticonvulsant

drugs in experimental animals (In Epilepsy Research Work).

The drug acts as a convulsant by interfering with chloride conductance.It binds to

an allosteric site on the GABAA receptor and acts as a negative modulator.

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Doxapram Hydrochloride ( Dopram): It stimulates respiration by action on peripheral carotid chemoreceptors. It has use as a

respiratory stimulant postanesthetically, after CNS depressant drug overdose, in chronic

obstructive pulmonary diseases, and in the apneas (Occasionally used in pt. with acute

resp. failure).

Dopram is administered exclusively by intravenous injection. Because of the benzyl

alcohol content of the injectable formulation, Dopram must never be given to neonates.

Strychnine (spinal cord Stimulant): Strychnine is an indole alkaloid obtained from the seeds of the Indian tree Strychnos nux-

vomica.

Strychnine inhibits competitively and reversibly the inhibitory neurotransmitter glycine at

postsynaptic neuronal sites in the spinal cord and medulla. This results in unchecked

reflex stimulation of motor neurons affecting all the striated muscles.

Because the extensor muscles are relatively more powerful than the flexor muscles, they

predominate to produce generalized rigidity and tonic-clonic seizures. Death results from

anoxia and exhaustion.

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Psychomotor stimulants: SAR activity of psychomotor agents: Structural features for many of the agents can be visualized easily by considering that

within their structure, they contain a β-phenethylamine moiety, and this grouping can give

some selectivity for presynaptic or postsynaptic noradrenergic systems.

β-Phenethylamine, given peripherally, lacks central activity. Facile metabolic inactivation

by monoamine oxidases (MAOs) is held responsible.

Branching with lower alkyl groups on the carbon atom adjacent (α) to the amino nitrogen

increases CNS rather than peripheral activity (e.g., amphetamine, presumably by retarding

metabolism).

The dextro(S)-isomer of amphetamine is up to 10 times as potent as the levo(R)-isomer for

alerting activity and about twice as active as a psychotomimetic agent.

Hydroxylation of the ring or hydroxylation on the β-carbon (to the nitrogen) decreases

activity, largely by decreasing the ability to cross the blood brain barrier.

Halogenation (F, Cl, and Br) of the aromatic ring decreases sympathomimetic activity.

Other activities may increase. P-Chloroamphetamine has strong central serotoninergic

activity.

Methoxyl or methylenedioxy substitution on the ring tends to produce psychotomimetic

agents, suggesting tropism for dopaminergic (D2) receptors.

N-methylation increases activity (e.g,compare methamphetamine with

dextroamphetamine). Di-N-methylation decreases activity. Mono-N substituents larger than

methyl decrease excitatory properties.

Amphetamine Sulfate: Amphetamine, (±)-1-phenyl-2-aminopropane (Benzedrine), as the racemic mixture has a

higher proportion of cardiovascular effects than the dextro isomer. For most medical

uses, the dextrorotatory isomer is preferred.

Amphetamines include methamphetamine (meth) and phentermine.

Amphetamine is a commonly used street drug. It makes users feel very alert and have lots

of energy. Stimulants like amphetamine and methamphetamine can also make the user

feel very happy.

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Dextroamphetamine Sulfate and Dextroamphetamine Phosphate: Dextroamphetamine, (+)-(S)-methylphenethylamine, forms salts with sulfuric acid

(Dexedrine) and with phosphoric acids. The phosphate is the more water-soluble salt and

is preferred if parenteral administration is required.

The dextrorotatory isomer has the (S) configuration and fewer cardiovascular effects than

the levorotatory (R)-isomer. Additionally, it may be up to 10 times as potent as the (R)-

isomer as an alerting agent and about twice as potent a psychotomimetic agent. Although

it is a more potent psychotomimetic agent than the (R)-isomer, it has a better ratio of

alerting to psychotomimetic effects.

The psychotomimetic effects are linked to release of DA and activation of postsynaptic

receptors. D2 and mesolimbic D3 receptors would be involved.

Dextroamphetamine is a strongly basic amine, with values from 9.77 to 9.94 reported.

Absorption from the gastrointestinal tract occurs as the lipid-soluble amine. The drug is

not extensively protein bound.

Varying amounts of the drug are excreted intact under ordinary conditions. The amount is

insignificant under conditions of alkaline urine. Under conditions producing systemic

acidosis, 60% to 70% of the drug can be excreted unchanged. This fact can be used to

advantage in treating drug overdose.

Under most conditions, the bulk of a dose of dextroamphetamine is metabolized by N-

dealkylation to phenylacetone and ammonia. Phenylacetone is degraded further to

benzoic acid.

In experimental animals, about 5% of a dose accumulates in the brain, especially the

cerebral cortex, the thalamus, and the corpus callosum. It is first p-hydroxylated and then

β-hydroxylated to produce p-hydroxynorephedrine, which has been reported to be the

major active metabolite involved in NE and DA release.

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Methamphetamine Hydrochloride: Methamphetamine,(+)-1-phenyl-2-methylaminopropanehydrochloridedesoxyephedrine

hydrochloride (Desoxyn), is the N-methyl analog of dextroamphetamine.

It has more marked central and less peripheral action than dextroamphetamine.

It has a very high abuse potential, and by the intravenous route, its salts are known as

“speed.”

Medicinally acceptable uses of methamphetamine are analogous to those of

dextroamphetamine.

Methylphenidate Hydrochloride (Ritalin): Methylphenidate is a potent CNS stimulant. Indications include narcolepsy and

attention-deficit disorder.

Methylphenidate is the most commonly used medication for ADHD, which work by

increasing activity in the brain, particularly in areas that play a part in controlling

attention and behaviour.

Because methylphenidate has two asymmetric centers, there are four possible

isomers. Methylphenidate, probably largely via its p-hydroxy metabolite, blocks NE

reuptake, acts as a postsynaptic agonist, depletes the same NE pools as reserpine, and

has effects on dopaminergic systems, such as blocking DA reuptake.

Methylphenidate is an ester drug with interesting pharmacokinetic properties arising

from its structure. The pKa values are 8.5 and 8.8. The protonated form in the

stomach reportedly resists ester hydrolysis.

After absorption from the gastrointestinaltract, however, 80% to 90% of the drug is

hydrolyzed rapidly to inactive ritalinic acid. Another 2% to 5% of the racemate is

oxidized by liver microsomes to the inactive cyclic amide.

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Methylxanthines: The naturally occurring methylxanthines are caffeine, theophylline, and theobromine.

Caffeine is a widely used CNS stimulant.

Theophylline has some medical use as a CNS stimulant, but its CNS stimulant properties

are encountered more often as sometimes severe, and potentially life-threatening, side

effects of its use in bronchial asthma therapy.

Theobromine has very little CNS activity (probably because of poor physicochemical

properties for distribution to the CNS).

Because of central vasoconstrictive effects, caffeine has value in treating migraine and

tension headaches and may have actual analgesic properties.

The important use of theophylline and its preparations in bronchial asthma. Caffeine also

is reported to have valuable bronchodilating properties in asthma.

Caffeine and theophylline have pharmaceutically important chemical properties. Both are

weak Brønsted-Lowry bases. The reported pKa values are 0.8 and 0.6 for caffeine and 0.7

for theophylline. These values represent the basicity of the imino nitrogen at position 9.

As acids, caffeine has a pKa above 14, and theophylline, a pKa of 8.8.

Caffeine in blood is not highly protein bound; theophylline is about 50% bound.

Differences in the substituent at the 7-position may be involved.

Caffeine is more lipophilic than theophylline and reputedly achieves higher brain

concentrations.

The half-life of caffeine is 5 to 8 hours, and that of theophylline, about 3.5 hours. About

1% of each compound is excreted unchanged.

The compounds are metabolized in the liver. The major metabolite of caffeine is 1-

methyluric acid, and that of theophylline, 1, 3-dimethyluric acid. Neither compound is

metabolized to uric acid, and they are not contraindicated in gout.

These drugs act as both:

A. Competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP,

activate PKA (Protein kinase), inhibit TNF-α and leukotriene synthesis, and reduce

inflammation and innate immunity.

B. Nonselective adenosine receptor antagonists (A1, A2 and A3), which explains many of its

cardiac effects A2 receptors antagonist responsible for CNS stimulation & smooth

muscles relaxation ↓calcium in Smooth muscles↑ calcium in CNS & heart.

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Cocaine: Cocaine as a euphoriant–stimulant and drug of abuse could as well be discussed with

amphetamine and methamphetamine, with which it shares many biological properties. At

low doses, it produces feelings of well-being, decreased fatigue, and increased alertness.

Cocaine is blockade of reuptake of the monoamines (NE, serotonin and dopamine).

A phenethylamine moiety with added steric bulk may suffice for this action. An

interaction between a hydrogen atom on the nitrogen of the protonated form of cocaine

and oxygen of the benzoyl ester group, or alternatively, an interaction between the

unshared electron pair of the freebase nitrogen and the carbonyl of the benzoyl ester

group, could approximate this moiety.

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Antidepressants: Antidepressant therapy usually implies therapy directed against major depressive

disorders of the unipolar type and is centered on three groups of chemical agents: the

MAOIs, the monoamine reuptake inhibitors, and autoreceptor desensitizers and

antagonists.

A-Monoamine Oxidase Inhibitors: MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the

breakdown of monoamine neurotransmitters and thereby increasing their availability.

There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A

preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-

B preferentially deaminates phenethylamine and certain other trace amines; in contrast,

MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine

is equally deaminated by both types.

Patients taking MAOIs generally need to change their diets to limit or avoid foods and

beverages containing tyramine. Examples of foods and beverages with potentially high

levels of tyramine include liver and fermented substances, such as alcoholic beverages

and aged cheeses.

Tyramine leads to hypertensive crisis by increasing the release of norepinephrine (NE),

which causes blood vessels to constrict, When MAO-A is inhibited, though, NE levels

get too high, leading to dangerous increases in blood pressure.

Tranylcypromine Sulfate: Tranylcypromine sulfate, (±)-trans-2-phenylcyclopropylamine sulfate (Parnate), was

synthesized to be an amphetamine analog (visualize the -methyl of amphetamine

condensed onto the β-carbon atom). It does have some amphetamine-like properties,

which may be why it has more immediate CNS-stimulant effects than agents that act by

MAO inhibition alone.

Tranylcypromine is a mechanism-based inactivator. It is metabolized by MAO, with one

electron of the nitrogen pair lost to flavin. This, in turn, produces hemolytic fission of a

carbon–carbon bond of cyclopropane, with one electron from the fission pairing with the

remaining lone nitrogen electron to generate an imine (protonated) and with the other

residing on a methylene carbon.

Thus, a free radical is formed that reacts to form a covalent bond with the enzyme or with

reduced flavin to inactivate the enzyme.

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B- Monoamine Reuptake Inhibitors: Is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine

neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one

or more of the respective monoamine transporters (MATs), which include the serotonin

transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT).

The net effect of the drug is to increase the level of the monoamine in the synapse.

Sustained high synaptic levels of 5-HT, NE, or both appear to be the basis for the

antidepressant effect of these agents.

Tricyclic Antidepressants:

The TCAs are extremely lipophilic and, accordingly, very highly tissue bound outside the

CNS. Because they have anticholinergic and noradrenergic effects, both central and

peripheral side effects are often unpleasant and sometimes dangerous. In overdose, the

combination of effects, as well as a quinidine-like cardiac depressant effect, can be lethal.

Overdose is complicated because the agents are so highly protein bound that dialysis is

ineffective.

Imipramine Hydrochloride: It is also a close relative of the antipsychotic phenothiazines (replace the 10–11 bridge

with sulfur, and the compound is the antipsychotic agent promazine). It has weaker D2

postsynaptic blocking activity than promazine and mainly affects amines (5-HT, NE, and

DA) via the transporters. As is typical of dimethylamino compounds, anticholinergic and

sedative (central H1 block) effects tend to be marked.

Metabolic inactivation proceeds mainly by oxidative hydroxylation in the 2-position,

followed by conjugation with glucuronic acid of the conjugate. Urinary excretion

predominates (about 75%), but some biliary excretion (up to 25%) can occur, probably

because of the large nonpolar grouping. Oxidative hydroxylation is not as rapid or

complete as that of the more nucleophilic ring phenothiazine antipsychotics;

consequently, appreciable N-demethylation occurs, with a buildup of norimipramine (or

desimipramine).

The demethylated metabolite is less anticholinergic, less sedative, and more stimulatory

and is a SNERI.Consequently, a patient treated with imipramine has two compounds that

contribute to activity. Overall, the effect is nonselective 5-HT versus NE reuptake. The

activity of desimipramine or norimipramine is terminated by 2-hydroxylation, followed

by conjugation and excretion. A second N-demethylation can occur, which in turn is

followed by 2-hydroxylation, conjugation, and excretion

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Clomipramine Hydrochloride: Clomipramine (Anafranil) is up to 50 times as potent as imipramine in some bioassays.

The chloro replacing the H-substituent could increase potency by increasing distribution

to the CNS.

It might be conjectured that an H-bond between the protonated amino group (as in vivo)

and the unshared electrons of the chloro substituent might stabilize a β-arylamine–like

shape and give more efficient competition for the transporter. The drug is an

antidepressant. It is used in obsessive compulsive disorder, an anxiety disorder that may

have an element of depression.

Amitriptyline Hydrochloride: Amitriptyline is one of the most anticholinergic and sedative of the TCAs. Because it

lacks the ring-electron–enriching nitrogen atom of imipramine, metabolic inactivation

mainly proceeds not at the analogous 2-position but at the benzylic 10-position (i.e.,

toluene-like metabolism predominates).

Because of the 5- exocyclic double bond, E- and Z-hydroxy isomers are produced by

oxidation metabolism. Conjugation produces excretable metabolites. As is typical of the

dimethyl compounds, N-demethylation occurs, and nortriptyline is produced, which has a

less anticholinergic, less sedative, and more stimulant action than amitriptyline.

Nortriptyline is a SNERI; the composite action of drug and metabolite is nonselective.

Nortriptyline metabolic inactivation and elimination are like those of amitriptyline.

Amitriptyline Nortriptyline

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C- Selective Serotonin Reuptake Inhibitors: Structurally, the SSRIs differ from the tricyclics, in that the tricyclic system has been

taken apart in the center.

Many of the dimethylamino tricyclics are, in fact, SSRIs. Because they are extensively N-

demethylated in vivo to norcompounds, which are usually SNERIs, however, the overall

effect is not selective. Breaking up the tricyclic system breaks up an anticholinergic

pharmacophoric group and gives compounds with diminished anticholinergic effects.

Overall, this diminishes unpleasant CNS effects ad increases cardiovascular safety.

Instead, side effects related to serotonin predominate.

Fluoxetine (Prozac): In fluoxetine, protonated in vivo, the protonated amino group can H-bond to the ether

oxygen electrons, which can generate the β-arylamino–like group, with the other aryl

serving as the characteristic “extra” aryl. The S-isomer is much more selective for SERT

than for NET. The major metabolite is the N-demethyl compound, which is as potent as

the parent and more selective (SERT versus NET).

Therapy for 2 or more weeks is required for the antidepressant effect. Somatodendritic 5-

HT1A autoreceptor desensitization with chronic exposure to high levels of 5-HT is the

accepted explanation for the delayed effect for this and other serotonin reuptake

inhibitors.

Paroxetine (Paxil): In the structure of paroxetine (Paxil), an amino group, protonated in vivo could H-bond

with the –CH2–O– unshared electrons. A β-arylamine–like structure with an extra aryl

group results. The compound is a very highly selective SERT. As expected, it is an

effective antidepressant and anxiolytic

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Sertraline (Zoloft): Inspection of sertraline reveals the pharmacophore for SERT inhibition. The Cl

substituents also predict tropism for a 5-HT system. The depicted stereochemistry is

important for activity.

Citalopram (Celexa): Citalopram is a racemic mixture and is very SERT selective. The N-monodemethylated

compound is slightly less potent but is as selective. The aryl substituents are important

for activity. The ether function is important and probably interacts with the protonated

amino group to give a suitable shape for SERT binding.

Hallucinogens (psychotomimetic):

Tetrahydrocannabinol (THC) Tetrahydrocannabinoid is a depressant with apparent stimulant sensations arising from

depression of higher centers. The main psychoactive alkaloid contained in marijuana is

tetrahydrocannabinol (THC).

Many effects, reputedly subjectively construed as pleasant, are evident at low doses. At

higher doses, psychotomimetic actions, including dysphoria, hallucinations, and paranoia,

can be marked.

Structural features associated with activity among cannabis-derived compounds, the

phenolic OH is required for activity.

Two receptors for THC have been discovered. The relevant receptor for CNS actions is

CB1. CB2 occurs in immune tissues. The first natural ligand found for the receptor is the

amide derivative of arachidonic acid, anandamide. Other natural cannabinoids are

arachidonic acid 2-glycerol ester and 2-arachidonyl glycerol ether.

The endogenous cannabinoid system appears to function as a retrograde messenger

system at both stimulatory synapses and depressant synapses.

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Indicated in AID pts ….Losing weight.

Rimonabant (CB1 receptor antagonist) in clinical trials for treatment of Obesity

THC

Indolethylamines

Dimethyltryptamine: Dimethyltryptamine is a very weak hallucinogen, active only by inhalation or injection, with a

short duration of action. It possesses pronounced sympathomimetic (NE) side effects.

Psilocybin and Psilocin: Psilocybin is the phosphoric acid ester of psilocin and appears to be converted to psilocin

as the active species in vivo. It occurs in a mushroom, Psilocybe mexicana. Both drugs

are active orally, with a short duration of action.

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Phenylethylamines

Mescaline: Mescaline, 3,4,5-trimethoxyphenethylamine, is a much studied hallucinogen with many

complex effects on the CNS.

The oral dose required for its hallucinogenic effects is very high, as much as 500 mg of

the sulfate salt. The low oral potency probably results from facile metabolism by MAO,

α-Methylation increases CNS activity.The drugs 2,5-dimethoxy-4-methylamphetamine

(DOM),3,4-methylenedioxyamphetamine(MDA),and2,5-dimethyldicyanoquinonediimine

(DMDA; ecstasy) are extremely potent and are dangerous drugs of abuse.

An Agent Possessing both an Indolethylamine and Phenylethylamine Moiety:

(+)-Lysergic Acid Diethylamide: Both an indolethylamine group and a phenylethylamine group can be seen in the structure

of the extraordinarilypotent hallucinogen LSD.

Experimentally, LSD has marked effects on serotoninergic and dopaminergic neurons.

The bases for all of its complex CNS actions are not completely understood, however.

Recently, its actions have been suggested as being more typical of schizophrenic

psychotic reactions than the model based on amphetamine.

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Dissociative Agents:

Phencyclidine: It blocks glutaminergic N-methyl-D-aspartate receptors.

Phencyclidine was introduced as a dissociative anesthetic for animals. Its close

structural relative ketamine is still so used and may be used in humans .In

humans, PCP produces a sense of intoxication, hallucinogenic experiences not

unlike those produced by the anticholinergic hallucinogens, and often, amnesia

The drug affects many systems, including those of NE, DA, and 5-HT. It has been

proposed that PCP (and certain other psychotomimetics) produces a unique

pattern of activation of ventral tegumental area dopaminergic neurons.

The psychotic state produced by this drug is also cited as a better model than

amphetamine psychosis for the psychotic state of schizophrenia.

Newer Drugs:

Modafinil Armodafinil

Questions: Are Stimulants Addictive? How?